Puromycin based inhibitors of aminopeptidases for the potential treatment of hematologic malignancies

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Abstract

Substantial progress has been described in the study of puromycin and its analogs for antibiotic properties. However, the peptidase inhibitory activity of related analogs has not been explored as extensively. Specifically, inhibiting aminopeptidases for achieving antitumor effect has been sparsely investigated. Herein, we address this challenge by reporting the synthesis of a series of analogs based on the structural template of puromycin. We also present exhaustive biochemical and in vitro analyses in support of our thesis. Analyzing the structure–activity relationship revealed a steric requirement for maximum potency. Effective inhibitors of Puromycin–Sensitive Aminopeptidase (PSA) are disclosed here. These potential therapeutic agents display superior in vitro antitumor potency against two leukemic cell lines, as compared to known inhibitors of aminopeptidases.

Original languageEnglish (US)
Pages (from-to)325-336
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume139
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
This research was supported by the funds from the Center for Drug Design at the University of Minnesota.

Publisher Copyright:
© 2017 Elsevier Masson SAS

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • Acute lymphoblastic leukemia (ALL)
  • Acute myeloid leukemia (AML)
  • Amino acid deprivation response (AADR)
  • Aminopeptidase N (APN)
  • Aminopeptidases
  • Puromycin–sensitive aminopeptidase (PSA)

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